Oestradiol ameliorates monocrotaline pulmonary hypertension via NO, prostacyclin and endothelin-1 pathways.

Pulmonary hypertension continues to be a serious clinical problem with high mortality. As oestrogen is a potential vasodilator of the pulmonary circulation, this study examined the mechanisms by which 17ß-oestradiol improves monocrotaline (MCT)-induced pulmonary hypertension. Female Sprague-Dawley rats underwent bilateral ovariectomy or sham operations. The rats received MCT (50 mg·kg(-1)) and were treated with 17ß-oestradiol (1 mg·kg(-1) per day) for either 5 weeks or only from week 4 to week 5. Plasma 17ß-oestradiol concentrations were decreased in sham-operated, MCT-treated rats when compared with sham-operated rats (17.7 ± 4.7 versus 50.3 ± 15.4 pg·mL(-1); p=0.029). The 17ß-oestradiol anabolic enzyme cytochrome P450 (CYP)-19 was decreased by MCT treatment, while the catabolic enzymes CYP-1A1 and -1B1 were increased. Ovariectomised and MCT-treated rats had more severe pulmonary hypertension. 17ß-oestradiol suppressed pulmonary arterial smooth muscle cell proliferation and macrophage infiltration, and enhanced apoptosis by increasing nitric oxide (NO) and prostacyclin (prostaglandin (PG)I2) levels and reducing endothelin (ET)-1 levels. Phosphoinositide-3-kinase (PI3K) and Akt phosphorylations were markedly increased, but were inhibited by 17ß-oestradiol treatment in rats with pulmonary hypertension. Oestrogen deficiency may aggravate development of pulmonary hypertension. 17ß-oestradiol improved pulmonary hypertension via activation of the PI3K/Akt pathway to regulate NO, PGI2 and ET-1 expression.